The H3K4 Demethylase JARID1B Is a Luminal Breast Cancer Oncoprotein

Recurrent mutations in transcription factors that drive lineage-specific gene expression are common in breast cancer, indicating that aberrant differentiation contributes to tumorigenesis. In addition, histone-modifying enzymes, such as lysine-specific demethylase 5B (KDM5B, also known as JARID1B), a histone H3 lysine 4 (H3K4) demethylase, regulate epithelial cell differentiation and are frequently mutated in cancer, suggesting that altered epigenetic programs also promote tumorigenesis. Yamamoto, Wu, and colleagues found that JARID1B is amplified and overexpressed in breast cancer, in particular luminal subtype tumors. Depletion of JARID1B resulted in upregulation of basal-cell genes and suppressed the growth of estrogen receptor–positive (ER⁺) breast cancer cells; this growth arrest phenotype was dependent on increased TGFβ signaling in the absence of JARID1B. JARID1B exhibited distinct chromatin binding patterns in luminal and basal-like breast cancer subtypes and was enriched in the promoter and enhancer regions of genes highly expressed in luminal but not basal cells. In addition, JARID1B binding overlapped with H3K4 trimethylation (H3K4me3), regions of reduced DNA methylation, and binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overlapping binding of JARID1B and CTCF was associated with decreased H3K4me3 in luminal cells, suggesting that CTCF modulates JARID1B binding and activity and that this interaction is functionally relevant in this breast cancer subtype. Consistent with an oncogenic role for JARID1B in luminal tumors, elevated luminal JARID1B activity was correlated with poor clinical outcome and endocrine resistance in patients with ER⁺ breast cancer. Intriguingly, heterozygous JARID1B mutation in a basal-like cell line resulted in unique chromatin binding and gain of luminal gene expression. These results identify JARID1B as a driver of luminal gene expression and a tumor subtype–specific oncoprotein and suggest that inhibition of this epigenetic enzyme may be therapeutically beneficial in patients with ER⁺ breast cancer.

Yamamoto S, Wu Z, Russnes HG, Takagi S, Peluffo G, Vaske C, et al. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 2014;25:762–77.